Amiodarone pulmonary, neuromuscular and ophthalmological ...downloads.hindawi.com/journals/crj/2000/139581.pdf · Amiodarone pulmonary, neuromuscular and ophthalmological toxicity

Amiodarone pulmonary,neuromuscular and

ophthalmological toxicity

Karen EA Burns MD FRCPC1, Eugenia Piliotis MD2,Bertha M Garcia MD FRCPC FCAP3, Kathleen A Ferguson MD FRCPC FCCP4

1Divisions of Respirology and Critical Care, Department of Medicine, University of WesternOntario; 2Internal Medicine, Department of Medicine, University of Western Ontario;3Department of Pathology, University of Western Ontario; 4Division of Respirology,

Department of Medicine, University of Western Ontario, London, Ontario

Can Respir J Vol 7 No 2 March/April 2000 193

CASE REPORT

Correspondence and reprints: Dr Kathleen Ferguson, University Campus, London Health Sciences Centre, 339 Windermere Road,London, Ontario N6A 5A5. Telephone 519-663-3606, fax 519-663-8806, e-mail [email protected]

KEA Burns, E Piliotis, BM Garcia, KA Ferguson. Amio-darone pulmonary, neuromuscular and ophthalmologi-cal toxicity. Can Respir J 2000;7(2):193-197.

Amiodarone is an iodinated benzofuran derivative class IIIantiarrhythmic that is highly effective in suppressing ven-tricular and supraventricular arrhythmias. It is also associ-ated with an imposing side effect profile, which often limitsits use. Numerous adverse effects have been documentedincluding skin discolouration, photosensitivity, hepatitis,thyroid dysfunction, corneal deposits, pulmonary fibrosis,bone marrow suppression and drug interactions. These sideeffects are thought to be correlated with the total cumulativedose of amiodarone, but idiopathic reactions have been re-ported. The majority of adverse reactions resolve with dis-continuation of the drug; however, rapid progression mayoccur, which may be fatal. The present report documents apatient who had a combination of serious amiodarone tox-icities that, once recognized, were treated and eventuallyresulted in a good outcome.

Key Words: Amiodarone adverse effects; Drug-induced pulmo-

nary disease; Drug toxicity; Phospholipidosis

Toxicité ophtalmologique, neuromusculaire etpulmonaire de l’amiodarone

L’amiodarone est un antiarythmique de classe III dérivé d’unbenzofuranne iodé qui est très efficace pour supprimer lesarythmies ventriculaires et supraventriculaires. Cet agentpossède également un imposant profil d’effets secondaires,qui en limite souvent l’utilisation. Ainsi, on a documenté denombreux effets secondaires dont une décoloration de lapeau, une photosensibilité, des troubles hépatiques, desdysfonctions thyroïdiennes, des dépôts cornéens, une fibrosepulmonaire, une insuffisance médullaire et des interactionsmédicamenteuses. On pense que ces effets secondaires sonten corrélation avec la dose cumulative totale d’amiodarone,cependant, des réactions idiopathiques ont aussi étérapportées. La majorité des réactions indésirables serésolvent avec l’interruption du traitement; toutefois, uneprogression rapide des symptômes peut survenir et qui peutêtre mortelle. Le présent article rapporte le cas d’un patientaccusant une combinaison d’effets secondaires toxiques qui,une fois identifiés, ont été traités pour finalement aboutir àdes résultats cliniques favorables.

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A62-year-old man with known hypertension, hypercho-

lesterolemia, peripheral vascular disease, ischemic heart

disease, ventricular arrhythmias and chronic obstructive pul-

monary disease presented with a nine-month history of pro-

gressive dyspnea, lower extremity dysesthesias and weakness.

Further inquiry revealed a history of a productive cough,

fatigue and an 80 pack-year smoking history. He complained

of decreased visual acuity, weakness and distal paresthesias.

He had severe postprandial nausea and intractable vomiting,

and had lost approximately 18 kg. There was no history of

bowel or bladder dysfunction. He had a history of significant

alcohol consumption. His medications consisted of isosor-

bide dinitrate 30 mg once daily, enteric coated ASA 325 mg

once daily, pentoxifylline 400 mg bid, metoprolol succinate

50 mg bid, amiodarone 400 mg bid and diltiazem continu-

ous delivery 120 mg once daily. At the time of admission he

was experiencing low grade fevers, night sweats and dyspnea

at rest, and was confined to a wheelchair because of weakness

and ataxia. He was complaining of severe pain in his lower ex-

tremities, which was incompletely controlled with narcotics.

On examination, the patient had significant hip flexor

weakness, proximal lower extremity atrophy and tenderness

to palpation of the quadriceps muscle bilaterally. He showed

flaccid weakness and hyporeflexia of both lower extremities

associated with loss of vibration and pinprick sensation in a

stocking distribution. He also had evidence of decreased dex-

terity, myoclonus, weakness and hypotonia in his dominant

right upper extremity. His reflexes were preserved and Bab-

inski responses were negative. He had decreased visual acuity

in his left eye (20/50), with associated papillitis and diplopia at

the extremes of gaze. An examination of the respiratory system

was unremarkable. He was intubated after suffering an acute

respiratory arrest shortly after arrival at the hospital. His acute

respiratory deterioration was thought to be secondary to aspi-

ration related to postprandial vomiting. Numerous investiga-

tions were conducted to arrive at a diagnosis.

Chest radiography (Figure 1) showed opacities in the

apexes bilaterally along with left hilar lymphadenopathy.

The patient was documented to have a normal chest x-ray six

months before presentation. Multiple investigations had been

completed at the time of transfer to the intensive care unit. The

computed tomographic (CT) head scan, bone scan, carotid

Doppler, magnetic resonance imaging of the spine, serum pro-

tein electrophoresis, tuberculosis skin test, urinalysis and

vasculitic screen were normal. The lumbar puncture, V/Q

scan and bronchoscopy were nondiagnostic. A CT scan of

the chest confirmed multiple bilateral opacities, in particular,

apical masses (Figure 2), small left hilar nodes and normal

abdominal viscera, and revealed small bilateral pleural effu-

sions. A CT-guided fine needle lung aspiration of one of the

apical masses was nondiagnostic. Blood work revealed nor-

mocytic anemia with elevated acute phase reactants. An ultra-

sound of the abdomen showed gastric distention with no

evidence of pyloric obstruction. The differential diagnoses in-

cluded primary lung cancer with an associated paraneoplastic

syndrome, systemic vasculitis and drug-induced lung disease.

Repeat bronchoscopy showed marked neutrophilia with

negative microbiology and cytology specimens. Upper

gastrointestinal endoscopy was normal. Electromyography

revealed sensorimotor polyneuropathy, with predominant

demyelinating features. Open lung, nerve and muscle

biopsies were performed under general anesthesia to

establish a definitive diagnosis. The open lung biopsy (Fig-

ures 3, 4) showed fibrosis of bronchioles and interstitium,

foci of obliterative bronchiolitis, thickening of alveolar

walls, numerous foamy macrophages and hyperplastic type

II cells. A sural nerve biopsy confirmed a demyelinating neu-

ropathy with severe secondary axonal degeneration (not

shown). Electron microscopic review of the nerve biopsy re-

vealed numerous lysosome-like inclusions within Schwann,

fibroblastic and endothelial cells compatible with amio-

darone neuropathy (not shown). A right vastus lateralis mus-

cle biopsy (Figure 5) showed type II atrophy with

vacuolization. The biopsy results supported the suspicion of

amiodarone toxicity.

The patient had a lengthy stay in the intensive care unit

complicated by nosocomial pneumonia, sepsis, unstable

angina and Clostridium difficile diarrhea. The amiodarone

194 Can Respir J Vol 7 No 2 March/April 2000

Burns et al

Figure 1) A chest radiograph showing apical pulmonary lesionsand left hilar lymphadenopathy

Figure 2) A computed tomographic scan showing masses in bothapexes

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was discontinued after a total of 10 months of therapy, and

intravenous methylprednisolone 100 mg every 6 h for five

days was administered. After a gastrojejunal tube was in-

serted, oral prednisone was initiated at a dose of 50 mg once

daily for four weeks followed by a tapering schedule of 5 mg

every two weeks.Once the diagnosis was established and

steroid therapy begun, the patient’s clinical status improved

significantly. His dysesthesias diminished, and he regained

strength in his lower limbs. Dramatic radiographic resolution

of the multifocal opacities occurred over three weeks. He was

breathing independently within one week. He was dis-

charged to his home hospital for intensive rehabilitation four

weeks after the initiation of steroid therapy.

On follow-up, pulmonary function testing revealed a

combined mild obstructive and restrictive pattern with a

forced expiration volume in 1 s of 2.4 L (69% of predicted),

forced vital capacity of 3.6 L (72% of predicted) and a diffus-

ing capacity corrected for lung volume of 3.1 L/min/mmHg

(59% of predicted). On neurological examination, he showed

better than antigravity strength in all upper limb muscles,

with a return of deep tendon reflexes to the biceps and

brachioradialis on the right. The lower limbs showed severe

muscle atrophy and weakness, with the right greater than the

left. Muscle strength testing revealed Medical Research

Council grades 2 to 4, with distal muscles weaker than proxi-

mal muscles. Vibration sense remained absent at the ankles,

and light touch was absent up to the knees bilaterally. Deep

tendon reflexes were absent in the lower extremities.

DISCUSSIONAmiodarone toxicity is often a diagnosis of exclusion,

with improvement after drug withdrawal (1). The presenting

features are nonspecific and may masquerade as an occult

malignancy. Several studies in the literature describe the fea-

tures of amiodarone toxicity; however, there is no reliable di-

agnostic tool to aid in early detection. We believe that our

patient exhibited at least three pulmonary manifestations of

amiodarone-induced pulmonary toxicity (AIPT), including

mass lesions, interstitial fibrosis and obliterative bronchioli-

tis. He also showed rare neurological involvement, including

neuromuscular toxicity, optic neuritis and probable auto-

nomic gastroparesis.

Pulmonary toxicity: The clinical presentation of AIPT can

be indolent and present a diagnostic challenge. Patients have

cough, dyspnea, fever, weight loss, chest pain and rarely he-

moptysis (2). These symptoms may occur from six days up to

60 months after the initiation of treatment, but most often oc-

cur in the first 12 months (3). AIPT occurs in 5% to 15% of

patients on amiodarone and can be fatal in up to a third of

those affected. Increasing age and pre-existing lung disease

may predispose patients to AIPT, but no tests or clinical fea-

tures can predict which patient will develop AIPT. The total

cumulative dose, and higher daily maintenance doses, have

been associated more consistently with an increased inci-

dence of AIPT. However, pulmonary toxicity has been re-

ported with short courses of low dose amiodarone (2).

Noninvasive pulmonary investigations are not reliable pre-


Amiodarone toxicity

Figure 3) A lung biopsy (elastic trichrome stain) demonstratingextensive parenchymal fibrosis, foci of obliterative bronchiolitis,thickened alveolar walls and foamy macrophages. Original magnifi-cation ��

Figure 4) A lung biopsy specimen (Hematoxylin & Eosin stain)showing foamy macrophages in the alveoli consistent with amio-darone effect. Original magnification ��

Figure 5) A right vastus lateralis muscle biopsy (adenosine triphos-phatase stain – pH 9.4) showing type 2 muscle fibre atrophy. Originalmagnification ��

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dictors of the development of AIPT. However, a decrease in

diffusing capacity by more than 20% should prompt closer

investigation (4).

Manifestations of AIPT described include bronchiolitis

obliterans with or without organizing pneumonia, chronic

interstitial pneumonitis with or without fibrosis, solitary or

multiple pulmonary masses or adult respiratory distress syn-

drome (1). CT scans may reveal high attenuation lesions in

the lung parenchyma as well as in the liver and spleen,

reflecting the accumulation of iodine in these tissues (5). The

diffusing capacity may be decreased or the alveolar-arterial

oxygen gradient may be increased (4). Bronchoalveolar

lavage (BAL) features may include an increase in total phos-

pholopid (phospholipid serine and phosphatidylinositol)

content, but more often, BAL reveals a nondiagnostic

increase in cellularity (6). Foam cells in a BAL are not diag-

nostic of AIPT because they are present in exposed individu-

als without toxicity, but their absence makes the diagnosis

unlikely (1). Tissue examination reveals fibrosis, nonspecific

interstitial pneumonitis, type II cell hyperplasia and foamy

macrophages. However, biopsy cannot distinguish between

exposure and toxicity (7).

The mechanism of AIPT is not clear. Amiodarone and its

metabolites may cause direct toxic cellular damage through

the inhibition of phospholipase A, resulting in cell membrane

and organelle dysfunction. Cultured lymphocytes exposed to

high concentrations of amiodarone show damage to mito-

chondrial membranes through the release of lactate

dehydrogenase (8). Amiodarone may lead to the formation of

toxic oxygen free radical species. Furthermore, amiodarone

may induce its toxic effects indirectly through immune modu-

lation or T cell-mediated hypersensitivity pneumonitis (9).

The treatment of AIPT is withdrawal of the drug with or

without corticosteroid therapy. There are case reports of

spontaneous remission of AIPT following early detection

and discontinuation of the drug, but a prolonged course of

corticosteroids is usually required. There are several reports

of steroid-dependent and steroid-resistant cases where AIPT

is fatal, and reports of symptomatic improvement while

maintaining patients on lower doses of amiodarone if alter-

native treatments for lethal arrhythmia are not available (2).

Neuromuscular and ophthalmological toxicity: Evidence

supporting the toxicity of amiodarone and its metabolites to

the neuromuscular and ophthalmological systems is accumu-

lating in the literature. Palakurthy and colleagues (10)

reported a high prevalence of neurotoxicity (approximately

45%) in 102 patients treated with amiodarone. Forty-five

patients treated with amiodarone for 9±8 months developed

tremor (44 patients), peripheral neuropathy (10 patients),

ataxia (seven patients) and proximal myopathy (four

patients). Neurophysiological studies showed varying

degrees of demyelinating peripheral neuropathy. Neither age

nor total cumulative dose was a risk factor for the develop-

ment of neuromuscular toxicity (10). Others have studied

nerve changes documenting both sensorimotor neuropathy

and predominantly motor involvement characterized by

demyelination with mild axonal loss (11). Other neurological

manifestations described include tremor, ataxia, peripheral

neuropathy, dyskinesia, myoclonic jerks, extrapyramidal

hypertony and altered mental status. Tremor and ataxia with

or without peripheral neuropathy were noted in

approximately half the patients in one study. Neurological

side effects improved or resolved within one month of dis-

continuing or decreasing amiodarone therapy (12). Ad-

vanced age, diabetes mellitus, renal failure and alcoholism

appeared to be risk factors for the development of amio-

darone neurotoxicity (13).

Rats given 50 mg/kg/day of amiodarone accumulated

lipid in lysosomes. Interestingly, these inclusions were

absent in regions with blood-nerve or blood-brain barriers.

Of regions outside the vascular barrier, autonomic ganglia

were most often affected, followed by the myenteric plexus

(14). Costa-Jussa and coworkers (15) studied the effects of

amiodarone in denervated skeletal muscle of mice. They

noted the development of a myopathy characterized by phos-

pholipid inclusions and vacuolization with sparing of type 1

fibres. Necrosis affected mainly type 2 fast twitch, high oxi-

dative enzyme activity fibres.

The predominant features of myopathic involvement are

proximal muscle weakness, increased enzyme levels and

associated electromyographic and histological changes. A

vacuolar myopathy is most frequently described (16,17).

Type 2 atrophy has also been reported in addition to a rare

necrotizing myopathy (18).

Ocular toxicity is extremely common, with asymptomatic

corneal microdeposits noted in all 140 patients in one retro-

spective series (19). Coloured haloes surrounding light

sources is a commonly reported symptom. On examination,

opacities may be found on the cornea, retina, lens and optic

nerves (13,20). Amiodarone has been associated with optic

neuropathy (21), and impaired visual acuity secondary to

papilledema and papillopathy.

CONCLUSIONSThis case presented a diagnostic challenge; it is unique in

that the patient showed at least three of the four pulmonary

manifestations of amiodarone toxicity. He also developed

autonomic gastroparesis, a demyelinating sensorimotor poly-

neuropathy, proximal myopathy and ophthalmological

involvement. An adequate lung biopsy to rule out other possi-

ble etiologies of pulmonary mass lesions in the presence of

neuromuscular deterioration is essential. Phospholipid inclu-

sions alone are not diagnostic; however, in the presence of

parenchymal fibrosis and the appropriate clinical setting, this

may be highly suggestive of AIPT. The use of corticosteroids

resulted in dramatic resolution of our patient’s radiographic

abnormalities and significant improvement in muscle

strength. We believe that our patient will ultimately regain

strength in his lower extremities similar to the clinical course

of patients with Guillain-Barré Syndrome.

ACKNOWLEDGEMENTS: The authors thank Dr AngelikaHahn and Dr Linda Hutton for their invaluable contributions to theneurological and radiographical aspects of this case.

196 Can Respir J Vol 7 No 2 March/April 2000

Burns et al

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Recognition and pathogenesis. Chest 1988;93:1067-75.2. Jessurun GA, Boersma WG, Crijns HJ. Amiodarone-induced

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3. Dusman RE, Stanton MS, Miles WM, et al. Clinical features ofamiodarone-induced pulmonary toxicity. Circulation 1990;82:51-9.

4. Ulrik CS, Backer V, Aldershvile J, Pietersen AH. Serial pulmonaryfunction tests in patients treated with low-dose amiodarone.Am Heart J 1992;123:1550-4.

5. Kuhlman JE, Teigen C, Ren H, et al. Amiodarone pulmonary toxicity:CT findings in symptomatic patients. Radiology 1990;177:121-5.[published erratum appears in Radiology 1991;178:287]

6. Nicolet-Chatelain G, Prevost MC, Escamilla R, Migueres J. Amiodarone-induced pulmonary toxicity. Immunoallergologic tests andbronchoalveolar lavage phospholipid content. Chest 1991;99:363-9.

7. Dean PJ, Groshart KD, Porterfield JG, Iansmith DH, Golden EB Jr.Amiodarone-associated pulmonary toxicity. A clinical and pathologicstudy of eleven cases. Am J Clin Pathol 1987;87:7-13.

8. Yasuda SU, Sausville EA, Hutchins JB, Kennedy T, Woosley RL.Amiodarone-induced lymphocyte toxicity and mitochondrial function.J Cardiovasc Pharmacol 1996;28:94-100.

9. Reasor MJ, Kacew S. An evaluation of possible mechanismsunderlying amiodarone-induced pulmonary toxicity. Proc Soc Exp BiolMed 1996;212:297-304.

10. Palakurthy PR, Iyer V, Meckler RJ. Unusual neurotoxicity associatedwith amiodarone therapy. Arch Intern Med 1987;147:881-4.

11. Jacobs JM, Costa-Jussa FR. The pathology of amiodaroneneurotoxicity. II. Peripheral neuropathy in man. Brain 1985;108:753-69.

12. Charness ME, Morady F, Scheinman MM. Frequent neurologic toxicityassociated with amiodarone therapy. Neurology 1984;34:669-71.

13. Arnaud A, Neau JP, Rivasseau-Jonveaux T, Marechaud R, Gil R.[Neurological toxicity of amiodarone. 5 case reports]. Rev Med Interne1992;6:419-22.

14. Costa-Jussa FR, Jacobs JM. The pathology of amiodaroneneurotoxicity. Experimental studies with reference to changes in othertissues. Brain 1985;108:735-52.

15. Costa-Jussa FR, Guevara A, Brook GA, Duchen LW, Jacobs JM.Changes in denervated skeletal muscle of amiodarone-fed mice. MuscleNerve 1988;11:627-37.

16. Le Quintrec JS, Le Quintrec JL. Drug-induced myopathies. BaillieresClin Rheumatol 1991;5:21-38.

17. Carella F, Riva E, Morandi L, Cappiello E, Mangoni A. Myopathyduring amiodarone treatment: a case report. Ital J Neurol Sci1987;8:605-8.

18. Clouston PD, Donnelly PE. Acute necrotising myopathy associatedwith amiodarone therapy. Aust NZJ Med 1989;19:483-5.

19. Harris L, McKenna WJ, Rowland E, Krikler DM. Side effects andpossible contraindications of amiodarone use. Am Heart J1983;106:916-23.

20. Mantyjarvi M, Tuppurainen K, Ikaheimo K. Ocular side effects ofamiodarone. Surv Ophthalmol 1998;42:360-6.

21. Feiner LA, Younge BR, Kazmier FJ, Stricker BH, Fraunfelder FT.Optic neuropathy and amiodarone therapy. Mayo Clin Proc1987;62:702-17.


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